Changes in the response to diuretics occur in subjects treated with indomethacin and in patients with congestive heart failure, liver disease, nephrotic syndrome and chronic renal failure. Resistance to diuretics could occur by several mechanisms: 1) Decreased delivery of drug to the active site. Pilot studies reported herein demonstrate this not to be the case with indomethacin treatment or in CHF; 2) Decreased delivery of solute to the site of diuretic action caused by decreased filtration and/or increased proximal reabsorption, the latter of which could involve a tubular effect or an indirect hemodynamic effect which could be affected by indomethacin or in disease; 3) Increased solute reabsorption distal to the site of action of the diuretic. This mechanism does not appear to be operative in the resistance to furosemide that occurs with indomethacin or in CHF; 4) Changed diuretic-receptor-mediator-response relationship. This mechanism may be operative in both CHF and with indomethacin treatment. This proposal will describe studies aimed at 1) Delineating the site of effect of indomethacin on solute transport in the nephron; 2) Clarifying the mechanism of the indomethacin-furosemide interaction; 3) Assessing dose-response curves to furosemide in disease states additional to CHF; 4) Defining the physiologic importance of different portions of the dose-response curve to furosemide by assessing changes in the dose-response relationship with coadministration of agents affecting different segments of the nephron; and 5) Assessing the relationship between severity of disease, changes in disposition of furosemide, and changes in response. We propose to attain these objectives by using measures of furosemide as a probe during renal clearance studies.